EP 0 720 982 B1 discloses the preparation of candesartan cilexetil by the deprotection of the triphenylmethane (trityl) moiety, in methanol and in the presence of hydrochloric acid. The setbacks of this procedure are very low yields and the product needs to be purified by means of chromatography. EP 0 668 272 further teaches an improved deprotection procedure by using anhydrous hydrogen chloride in methanol. The yields are slightly improved in respect to EP 0 720 982 B1 but nonetheless the proportion of the decomposition products is still rather high. The drawbacks of the above mentioned methods are that they include the use of strongly corrosive acids and also the need to process the reaction mixture by complex extractions or chromatographic purification.
WO 2005/021535 discloses the preparation of candesartan cilexetil by the deprotection of the trityl moiety by solvolysis at reflux temperatures, in an anhydrous C1 to C5 alcohol under neutral or slightly basic conditions. The reported conversion to candesartan cilexetil is between 76% and 91% which is still not optimal in industrial production, and the reported reaction time is 24 hours, which is another setback from the industrial point of view. Further on, longer reaction times at reflux temperatures normally lead to higher levels of decomposition products.
WO 2005/037821 describes the deprotection of the tetrazolyl group from (+/−)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (trityl candesartan cilexetil) by the use of methanesulfonic, p-toluene sulphonic, formic, and trifluoroacetic acid, or simply by refluxing trityl candesartan cilexetil in a mixture of toluene, methanol, and water. The drawbacks of these procedures are that the deprotection reaction is not completed properly and that the product is mostly isolated in form of a viscous oil due to impurities present.
WO 2005/051928 teaches processes for the production of tetrazolyl compounds including removing protective groups from an N-protected tetrazolyl compound, especially candesartan cilexetil, with organic acids. As low reaction temperatures, from 30° C. to 35° C. are applied, the yields are not higher that 60% and additional extractions and purifications with activated charcoal and by means of Celite are applied which is a clear sign for the presence of unwished side products and/or the presence of the starting material.